Chronic Neuropsychological Sequelae of Cholinesterase Inhibitors in the Absence of Structural Brain Damage: Two Cases of Acute Poisoning

Here we describe two cases of carbamate poisoning. Patients AMF and PVM were accidentally poisoned by cholinesterase inhibitors. The medical diagnosis in both cases was overcholinergic syndrome, as demonstrated by exposure to cholinesterase inhibitors. The widespread use of cholinesterase inhibitors, especially as pesticides, produces a great number of human poisoning events annually. The main known neurotoxic effect of these substances is cholinesterase inhibition, which causes cholinergic overstimulation. Once AMF and PVM had recovered from acute intoxication, they were subjected to extensive neuropsychological evaluation 3 and 12 months after the poisoning event. These assessments point to a cognitive deficit in attention, memory, perceptual, and motor domains 3 months after intoxication. One year later these sequelae remained, even though the brain magnetic resonance imaging (MRI) and computed tomography (CT) scans were interpreted as being within normal limits. We present these cases as examples of neuropsychological profiles of long-term sequelae related to acute poisoning by cholinesterase inhibitor pesticides and show the usefulness of neuropsychological assessment in detecting central nervous system dysfunction in the absence of biochemical or structural markers

SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes

Diabetic kidney disease (DKD) is a topic of increasing concern among clinicians involved in the management of type 2 diabetes mellitus (T2DM). It is a progressive and costly complication associated with increased risk of adverse cardiovascular (CV) and renal outcomes and mortality. Ongoing monitoring of the estimated glomerular filtration (eGFR) rate alongside the urine albumin:creatinine ratio (ACR) is recommended during regular T2DM reviews to enable a prompt DKD diagnosis or to assess disease progression, providing an understanding of adverse risk for each individual. Many people with DKD will progress to end-stage kidney disease (ESKD), requiring renal replacement therapy (RRT), typically haemodialysis or kidney transplantation. A range of lifestyle and pharmacological interventions is recommended to help lower CV risk, slow the advancement of DKD and prevent or delay the need for RRT. Emerging evidence concerning sodium-glucose co-transporter-2 inhibitor (SGLT2i) agents suggests a role for these medicines in slowing eGFR decline, enabling regression of albuminuria and reducing progression to ESKD. Improvements in renal end points observed in SGLT2i CV outcome trials (CVOTs) highlighted the possible impact of these agents in the management of DKD. Data from the canagliflozin CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) have since demonstrated the effectiveness of this medicine in reducing the risk of kidney failure and CV events in a population comprising individuals with T2DM and renal disease. CREDENCE was the first SGLT2i study to examine renal outcomes as the primary end point. Real-world studies have reaffirmed these outcomes in routine clinical practice. This article summarises the evidence regarding the use of SGLT2i medicines in slowing the progression of DKD and examines the possible mechanisms underpinning the renoprotective effects of these agents. The relevant national and international guidance for monitoring and treatment of DKD is also highlighted to help clinicians working to support this vulnerable group

The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review

Over recent years, the expanding evidence base for sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapies has revealed benefits beyond their glucose-lowering efficacy in the treatment of Type 2 diabetes mellitus (T2DM), resulting in their recognition as cardiorenal medicines. While SGLT2is continue to be recommended among the second-line therapies for the treatment of hyperglycaemia, their true value now extends to the prevention of debilitating and costly cardiovascular and renal events for high-risk individuals, with particular benefit shown in reducing major adverse cardiac events and heart failure (HF) and slowing the progression of chronic kidney disease. However, SGLT2i usage is still suboptimal among groups considered to be at greatest risk of cardiorenal complications. The ongoing coronavirus disease 2019 (COVID-19) pandemic has intensified financial pressures on healthcare systems, which may hamper further investment in newer effective medicines. Emerging evidence indicates that glycaemic control should be prioritised for people with T2DM in the era of COVID-19 and practical advice on the use of T2DM medications during periods of acute illness remains important, particularly for healthcare professionals working in primary care who face multiple competing priorities. This article provides the latest update from the Improving Diabetes Steering Committee, including perspectives on the value of SGLT2is as cost-effective therapies within the T2DM treatment paradigm, with particular focus on the latest published evidence relating to the prevention or slowing of cardiorenal complications. The implications for ongoing and future approaches to diabetes care are considered in the light of the continuing coronavirus pandemic, and relevant aspects of international treatment guidelines are highlighted with practical advice on the appropriate use of SGLT2is in commonly occurring T2DM clinical scenarios. The ‘SGLT2i Prescribing Tool for T2DM Management’, previously published by the Steering Committee, has been updated to reflect the latest evidence and is provided in the Supplementary Materials to help support clinicians delivering T2DM care

PAKs supplement improves immune status and body composition but not muscle strength in resistance trained individuals

Mixed formula supplements are very popular among recreational and professional weightlifters. They are usually known as PAKs and they are supposed to have a synergistic effect of their different nutrients. The purpose of this study was to determine the effects of chronic (4 weeks) PAKS supplementation in combination with strength training on body composition, immune status and performance measures in recreationally trained individuals with or without PAKs supplementation. Methods: Twelve male subjects (Placebo n = 6 and PAKs supplement n = 6) were recruited for this study. The body composition, one maximum strength repetition tests and immune status were assessed before and after 4 week supplementation. Our data showed that, 4 week PAK supplementation associated with strength exercise not was effective in change strength than compared with placebo group. However, we observed that, PAK supplement was able to improve immune status and reduced body composition when compared with placebo group. These results indicate that, a mixed formula supplement is able to improve immune status and body composition but not maximum strength in recreational strength trained subjects in a 4 weeks period

Gene expression and splicing alterations analyzed by high throughput RNA sequencing of chronic lymphocytic leukemia specimens.

BackgroundTo determine differentially expressed and spliced RNA transcripts in chronic lymphocytic leukemia specimens a high throughput RNA-sequencing (HTS RNA-seq) analysis was performed.MethodsTen CLL specimens and five normal peripheral blood CD19+ B cells were analyzed by HTS RNA-seq. The library preparation was performed with Illumina TrueSeq RNA kit and analyzed by Illumina HiSeq 2000 sequencing system.ResultsAn average of 48.5 million reads for B cells, and 50.6 million reads for CLL specimens were obtained with 10396 and 10448 assembled transcripts for normal B cells and primary CLL specimens respectively. With the Cuffdiff analysis, 2091 differentially expressed genes (DEG) between B cells and CLL specimens based on FPKM (fragments per kilobase of transcript per million reads and false discovery rate, FDR q < 0.05, fold change >2) were identified. Expression of selected DEGs (n = 32) with up regulated and down regulated expression in CLL from RNA-seq data were also analyzed by qRT-PCR in a test cohort of CLL specimens. Even though there was a variation in fold expression of DEG genes between RNA-seq and qRT-PCR; more than 90 % of analyzed genes were validated by qRT-PCR analysis. Analysis of RNA-seq data for splicing alterations in CLL and B cells was performed by Multivariate Analysis of Transcript Splicing (MATS analysis). Skipped exon was the most frequent splicing alteration in CLL specimens with 128 significant events (P-value <0.05, minimum inclusion level difference >0.1).ConclusionThe RNA-seq analysis of CLL specimens identifies novel DEG and alternatively spliced genes that are potential prognostic markers and therapeutic targets. High level of validation by qRT-PCR for a number of DEG genes supports the accuracy of this analysis. Global comparison of transcriptomes of B cells, IGVH non-mutated CLL (U-CLL) and mutated CLL specimens (M-CLL) with multidimensional scaling analysis was able to segregate CLL and B cell transcriptomes but the M-CLL and U-CLL transcriptomes were indistinguishable. The analysis of HTS RNA-seq data to identify alternative splicing events and other genetic abnormalities specific to CLL is an added advantage of RNA-seq that is not feasible with other genome wide analysis

Transient pulsed radio emission from a magnetar

Anomalous X-ray pulsars (AXPs) are slowly rotating neutron stars with very bright and highly variable X-ray emission that are believed to be powered by ultra-strong magnetic fields of >1e14 G, according to the 'magnetar' model. The radio pulsations that have been observed from more than 1,700 neutron stars with weaker magnetic fields have never been detected from any of the dozen known magnetars. The X-ray pulsar XTE J1810-197 was revealed (in 2003) as the first AXP with transient emission when its luminosity increased 100-fold from the quiescent level; a coincident radio source of unknown origin was detected one year later. Here we show that XTE J1810-197 emits bright, narrow, highly linearly polarized radio pulses, observed at every rotation, thereby establishing that magnetars can be radio pulsars. There is no evidence of radio emission before the 2003 X-ray outburst (unlike ordinary pulsars, which emit radio pulses all the time), and the flux varies from day to day. The flux at all radio frequencies is approximately equal -- and at >20 GHz XTE J1810-197 is currently the brightest neutron star known. These observations link magnetars to ordinary radio pulsars, rule out alternative accretion models for AXPs, and provide a new window into the coronae of magnetars.Comment: accepted by Nature; some new data and significantly revised discussio

No contribution of GSTM1 and GSTT1 null genotypes to the risk of neutropenia due to benzene exposure in Southeastern Brazil

Exposure to benzene has been associated with haematological diseases such as neutropenia (NEB) and acute myeloid leukaemia (AML). We tested whether the null genotypes of the GSTM1 and GSTT1 genes, involved in benzene inactivation, altered the risk for NEB in southeastern Brazil. Genomic DNA from 55 NEB patients and 330 controls was analysed by multiplex-polymerase chain reaction. The frequency of the GSTM1, GSTT1 and combined null genotypes was similar in patients and controls (GSTM1, 27.3% vs. 38.8%, p = 0.16; GSTT1, 25.5% vs. 19.7%, p = 0.24; GSTM1/GSTT1, 12.7% vs. 6.7%, p = 0.26; respectively). The distribution of genotype classes in NEB patients was similar to normal controls, suggesting that GSTM1 and GSTT1 null genotypes make no specific contribution to the risk of NEB. As the GSTM1 and GSTT1 null genotypes were previously associated with increased risk for AML in Brazil and elsewhere, we hypothesise that different thresholds of chemical exposure relative to distinct GSTM1 and GSTT1 genotypes may determine whether AML or NEB manifests in benzene exposed individuals from southeastern Brazil. Although indicative, our results still require support by prospective and large scale epidemiological studies, with rigorous assessment of daily chemical exposures and control of the possible contribution of other polymorphic genes involved in benzene metabolism

Towards an integrated crowdsourcing definition

Crowdsourcing is a relatively recent concept that encompasses many practices. This diversity leads to the blurring of the limits of crowdsourcing that may be identified virtually with any type of internet-based collaborative activity, such as co-creation or user innovation. Varying definitions of crowdsourcing exist, and therefore some authors present certain specific examples of crowdsourcing as paradigmatic, while others present the same examples as the opposite. In this article, existing definitions of crowdsourcing are analysed to extract common elements and to establish the basic characteristics of any crowdsourcing initiative. Based on these existing definitions, an exhaustive and consistent definition for crowdsourcing is presented and contrasted in 11 cases.Estelles Arolas, E.; González-Ladrón-De-Guevara, F. (2012). Towards an integrated crowdsourcing definition. Journal of Information Science. 32(2):189-200. doi:10.1177/0165551512437638S189200322Vukovic, M., & Bartolini, C. (2010). Towards a Research Agenda for Enterprise Crowdsourcing. Leveraging Applications of Formal Methods, Verification, and Validation, 425-434. doi:10.1007/978-3-642-16558-0_36Brabham, D. C. (2008). Crowdsourcing as a Model for Problem Solving. Convergence: The International Journal of Research into New Media Technologies, 14(1), 75-90. doi:10.1177/1354856507084420Vukovic, M. (2009). Crowdsourcing for Enterprises. 2009 Congress on Services - I. doi:10.1109/services-i.2009.56Doan, A., Ramakrishnan, R., & Halevy, A. Y. (2011). Crowdsourcing systems on the World-Wide Web. Communications of the ACM, 54(4), 86. doi:10.1145/1924421.1924442Brabham, D. C. (2008). Moving the crowd at iStockphoto: The composition of the crowd and motivations for participation in a crowdsourcing application. First Monday, 13(6). doi:10.5210/fm.v13i6.2159Huberman, B. A., Romero, D. M., & Wu, F. (2009). Crowdsourcing, attention and productivity. Journal of Information Science, 35(6), 758-765. doi:10.1177/0165551509346786Andriole, S. J. (2010). Business impact of Web 2.0 technologies. Communications of the ACM, 53(12), 67. doi:10.1145/1859204.1859225Denyer, D., Tranfield, D., & van Aken, J. E. (2008). Developing Design Propositions through Research Synthesis. Organization Studies, 29(3), 393-413. doi:10.1177/0170840607088020Egger, M., Smith, G. D., & Altman, D. G. (Eds.). (2001). Systematic Reviews in Health Care. doi:10.1002/9780470693926Tatarkiewicz, W. (1980). A History of Six Ideas. doi:10.1007/978-94-009-8805-7Cosma, G., & Joy, M. (2008). Towards a Definition of Source-Code Plagiarism. IEEE Transactions on Education, 51(2), 195-200. doi:10.1109/te.2007.906776Brabham, D. C. (2009). Crowdsourcing the Public Participation Process for Planning Projects. Planning Theory, 8(3), 242-262. doi:10.1177/1473095209104824Alonso, O., & Lease, M. (2011). Crowdsourcing 101. Proceedings of the fourth ACM international conference on Web search and data mining - WSDM ’11. doi:10.1145/1935826.1935831Bederson, B. B., & Quinn, A. J. (2011). Web workers unite! addressing challenges of online laborers. Proceedings of the 2011 annual conference extended abstracts on Human factors in computing systems - CHI EA ’11. doi:10.1145/1979742.1979606Grier, D. A. (2011). Not for All Markets. Computer, 44(5), 6-8. doi:10.1109/mc.2011.155Heer, J., & Bostock, M. (2010). Crowdsourcing graphical perception. Proceedings of the 28th international conference on Human factors in computing systems - CHI ’10. doi:10.1145/1753326.1753357Heymann, P., & Garcia-Molina, H. (2011). Turkalytics. Proceedings of the 20th international conference on World wide web - WWW ’11. doi:10.1145/1963405.1963473Kazai, G. (2011). In Search of Quality in Crowdsourcing for Search Engine Evaluation. Advances in Information Retrieval, 165-176. doi:10.1007/978-3-642-20161-5_17La Vecchia, G., & Cisternino, A. (2010). Collaborative Workforce, Business Process Crowdsourcing as an Alternative of BPO. Lecture Notes in Computer Science, 425-430. doi:10.1007/978-3-642-16985-4_40Liu, E., & Porter, T. (2010). Culture and KM in China. VINE, 40(3/4), 326-333. doi:10.1108/03055721011071449Oliveira, F., Ramos, I., & Santos, L. (2010). Definition of a Crowdsourcing Innovation Service for the European SMEs. Lecture Notes in Computer Science, 412-416. doi:10.1007/978-3-642-16985-4_37Porta, M., House, B., Buckley, L., & Blitz, A. (2008). Value 2.0: eight new rules for creating and capturing value from innovative technologies. Strategy & Leadership, 36(4), 10-18. doi:10.1108/10878570810888713Ribiere, V. M., & Tuggle, F. D. (Doug). (2010). Fostering innovation with KM 2.0. VINE, 40(1), 90-101. doi:10.1108/03055721011024955Sloane, P. (2011). The brave new world of open innovation. Strategic Direction, 27(5), 3-4. doi:10.1108/02580541111125725Wexler, M. N. (2011). Reconfiguring the sociology of the crowd: exploring crowdsourcing. International Journal of Sociology and Social Policy, 31(1/2), 6-20. doi:10.1108/01443331111104779Whitla, P. (2009). Crowdsourcing and Its Application in Marketing Activities. Contemporary Management Research, 5(1). doi:10.7903/cmr.1145Yang, J., Adamic, L. A., & Ackerman, M. S. (2008). Crowdsourcing and knowledge sharing. Proceedings of the 9th ACM conference on Electronic commerce - EC ’08. doi:10.1145/1386790.1386829Brabham, D. C. (2010). MOVING THE CROWD AT THREADLESS. Information, Communication & Society, 13(8), 1122-1145. doi:10.1080/13691181003624090Giudice, K. D. (2010). Crowdsourcing credibility: The impact of audience feedback on Web page credibility. Proceedings of the American Society for Information Science and Technology, 47(1), 1-9. doi:10.1002/meet.14504701099Stewart, O., Huerta, J. M., & Sader, M. (2009). Designing crowdsourcing community for the enterprise. Proceedings of the ACM SIGKDD Workshop on Human Computation - HCOMP ’09. doi:10.1145/1600150.1600168Maslow, A. H. (1943). A theory of human motivation. Psychological Review, 50(4), 370-396. doi:10.1037/h0054346Veal, A. J. (Ed.). (2002). Leisure and tourism policy and planning. doi:10.1079/9780851995465.0000Dahlander, L., & Gann, D. M. (2010). How open is innovation? Research Policy, 39(6), 699-709. doi:10.1016/j.respol.2010.01.01

Systemic chemotherapy induces microsatellite instability in the peripheral blood mononuclear cells of breast cancer patients

INTRODUCTION: Systemic chemotherapy is an important part of treatment for breast cancer. We conducted the present study to evaluate whether systemic chemotherapy could produce microsatellite instability (MSI) in the peripheral blood mononuclear cell fraction of breast cancer patients. METHODS: We studied 119 sequential blood samples from 30 previously untreated breast cancer patients before, during and after chemotherapy. For comparison, we also evaluated 20 women who had no relevant medical history (control group). RESULTS: In 27 out of 30 patients we observed MSI in at least one sample, and six patients had loss of heterozygosity. We found a significant correlation between the number of MSI events per sample and chemotherapy with alkylating agents (P < 0.0001). We also observed an inverse correlation between the percentage of cells positive for hMSH2 and the number of MSI events per sample (P = 0.00019) and use of alkylating agents (P = 0.019). CONCLUSION: We conclude that systemic chemotherapy may induce MSI and loss of heterozygosity in peripheral blood mononuclear cells from breast cancer patients receiving alkylating agents, possibly mediated by a chemotherapy-induced decrease in the expression of hMSH2. These effects may be related to the generation of secondary leukaemia in some patients, and may also intensify the genetic instability of tumours and increase resistance to treatment